Proximal Tubules Forget “Self-Eating” When They Meet Western Meals

Abstract

Autophagy is an evolutionarily conserved cellular catabolic process in which cytoplasmic components are isolated from the rest of the cell within double-membrane structures (autophagosomes) and degraded through lysosomal degradation. Autophagy is activated under conditions of metabolic stress in which there is a shortage of energy for cells to maintain cellular homeostasis. 1 A number of recent studies demonstrated that the induction of autophagy serves a crucial role in protecting renal proximal tubular cells from many stresses, including ischemia/ reperfusion and nephrotoxic agents. 2-4 However, few studies have examined the role of proteinuria in the regulation of autophagy and the conditions that impair the activity of autophagy in the course of renal dysfunction. By characterizing an albumin-overload mice model and tissues from obese patients with proteinuria, Yamahara and coworkers, as described in this issue of JASN, 5 present evidence that autophagy plays an important role in protecting renal proximal tubular cells from harmful proteinuria. They demonstrated that proteinuria is a strong cue for autophagy induction in the proximal tubular cells of mice with albumin overload. Furthermore, high-fat diet and obesity blunt proteinuria-induced autophagy induction in the proximal tubules and thereby exacerbate tubular cell damage by proteinuria.The term "autophagy" is derived from the Greek words "phagy," meaning eat, and "auto," meaning self. Interestingly, this "self-eating" behavior was first discovered in renal proximal tubular cells of newborn mice in 1957. 6 Dr. Clark described the observations of autophagy in his paper:The large round bodies in the proximal tubules consist of an amorphous material and contain concentrically lamellar structures and mitochondria. They resemble the cytoplasmic droplets produced in the proximal tubules of adult rats and mice by the administration of proteins. The large round bodies disappear from the proximal tubules of infant mice during the first week after birth, but the concentric lamellar structure may be found in adult mice.From these observations, Clark hypothesized that the formation of the large round bodies (autophagosome) in the proximal tubules was likely due to the absorption of proteins that passed through immature newborn glomeruli. Now, Yamahara and coworkers have re-evaluated the process of renal tubular autophagy first described more than a half-century ago using their modern technologies under clinically relevant conditions.Compared with control mice, mice lacking autophagy activity in the renal proximal tubular cells displayed more severe damage of their tubular cells in response to free fatty acid (FFA)-albumin-induced proteinuria. Furthermore, the renoprotective activity of proteinuria-induced autophagy in proximal tubular cells was suppressed in obese mice and humans. Yamahara and coworkers found that the activation of 59AMP-activating protein kinase (AMPK) but not the enhanced endoplasmic reticulum stress played a critical role in the induction of aut...